RT Journal Article
SR Electronic
T1 Tumor-released autophagosomes induces CD4<sup>+</sup> T cell-mediated immunosuppression via a TLR2–IL-6 cascade
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 178
DO 10.1186/s40425-019-0646-5
VO 7
IS 1
A1 Yong-Qiang Chen
A1 Peng-Cheng Li
A1 Ning Pan
A1 Rong Gao
A1 Zhi-Fa Wen
A1 Tian-Yu Zhang
A1 Fang Huang
A1 Fang-Yuan Wu
A1 Xi-Long Ou
A1 Jin-Ping Zhang
A1 Xue-Jun Zhu
A1 Hong-Ming Hu
A1 Kang Chen
A1 Yun-Lang Cai
A1 Li-Xin Wang
YR 2019
UL http://jitc.bmj.com/content/7/1/178.abstract
AB Background CD4+ T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4+ T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4+ T cells in the tumor microenvironment.Methods TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4+ T cells to examine the function and mechanism of TRAPs in CD4+ T cell differentiation and function. TRAPs-elicited CD4+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model.Results Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4+ T cell production of IL-6 via a TLR2–MyD88–NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4+ T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4+ T cells inhibited CD4+ and CD8+ effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4+ T cells markedly retarded tumor growth. Furthermore, B cell or CD4+ T cell depletion impeded tumor growth by increasing effector T cell function.Conclusions HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4+ T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.Yong-Qiang Chen, Peng-Cheng Li and Ning Pan contributed equally to this work.Abbreviations:APCsAntigen-presenting cellsBregsRegulatory B cellsCFSECarboxyfluorescein succinimidyl esterDAMPsDamage-associated molecular pattern moleculesdLNsDraining lymph nodesEVsExtracellular vesiclesHMGB1High mobility group box 1HSPHeat shock proteinKDKnock downKOKnock outmAbMonoclonal antibodyNSNormal salinePAMPsPathogen-associated molecular patternsPBMCPeripheral blood mononuclear cellROSReactive oxygen speciesTBTumor-bearingTFTumor-freeTLRsToll-like receptorsTRAPsTumor cell-released autophagosomesWTWild-type